Significance: Malignant melanoma is one of the lethal cancers known to man. Every year approximately 60,000 new melanoma patients are diagnosed in the USA of which ~8,000 die from this disease. Systemic chemotherapy is an important and essential modality for treatment of advanced melanoma. However, intolerable hepatotoxicity is a major drawback for successful chemotherapy of melanoma. Therefore, there is a clear and urgent need exists for developing novel and improved chemotherapeutics for melanoma. Objectives and Aims: The broad, long term objective of the applicant is to select and investigate various phenolic compounds as anti-melanoma drugs. The specific purpose of this proposal is to study the use of novel phenolic agents (PAs) as prodrugs for a selective melanoma targeting drug therapy using tyrosinase as a target enzyme. The central hypothesis of this proposal is that phenolic agents that are metabolized by tyrosinase but not by liver P450 enzymes will be effective against melanoma with no significant toxicity towards liver. The following 3 specific aims will be pursued in this study: 1) To delineate the biochemical basis of PAs toxicity toward melanoma cell lines, Aim 2) To characterize the biochemical basis of PAs toxicity toward rat hepatocytes, and Aim 3) To investigate in vivo liver toxicity and efficacy of PAs in mice to identify PAs devoid of liver toxicity. The role of P450 mediated induced toxicity will be also investigated. Research Design and Methods: We will use in-vitro models (enzyme assays, mouse and human melanoma cells, and rat liver cells) to study the metabolism, toxicology and efficacy of drugs, and the mice models to study PAs in vivo liver toxicity and in vivo efficacy. The animal protocols necessary to carry out this proposal have been approved by Institutional Animal Care & Use Committee. The rationale for this proposal is that phenolic agents which are metabolized by melanoma tyrosinase to toxic metabolites should kill only and selectively the melanoma cells with minimum or no liver toxicity due to the absence of their metabolism by liver enzymes. Relevance to Health: With increasing occurrence of melanoma and the absence of effective chemotherapy for this cancer there is a clear and urgent need for improved treatments with enhanced specificity. Public Health Relevance Statement: With increasing occurrence of melanoma and the absence of effective chemotherapy for this cancer there is a clear and urgent need to improve treatments with enhanced specificity and reduced toxicity. In this work we will be developing novel phenol based drugs for treatment of melanoma. [unreadable] [unreadable] [unreadable]